Cancers of the esophagogastric region are highly malignant tumours with five-year survival rates of less than sixteen percent (Sant et al., 2003). Research has shown that 88% of patients, selected for curative resection for esophagogastric cancer, already have disseminated tumour cells (O'Sullivan G et al., 1999), that can remain dormant for variable periods, before emerging as aggressive, drug resistant metastases (Ryan et al., 2004). Improved systemic therapeutic options are therefore required to effectively eliminate primary and recurrent esophageal cancer.
Chemotherapeutic regimes are designed to induce maximum cancer cell killing, by engaging a cell death program. Drug resistance due to a failure to adequately engage programmed cell death (PCD) leads to recurrence of cancer. This is a major limitation, as de-regulation of cell death programs often plays a role in the development of the cancer in the first place (Raguz and Yague, 2008). Previously, apoptosis (Type I cell death) was regarded as the central mediator of PCD in response to chemotherapeutic agents. However, other death programs exist in eukaryotic cells (Ricci and Zong, 2006, Degterev and Yuan, 2008). Type II cell death is characterised by the formation of vesicles in the cytoplasm, loss of the cytoplasmic material and pyknosis of nuclear material within an intact nuclear membrane (Clarke, 1990). Evidence suggests that this morphology is a consequence of excessive autophagy. Several studies have now reported autophagic cell death in cultured mammalian cells (Pattingre et al., 2005, Yu et al., 2006, Opipari et al., 2004, Scarlatti et al., 2008, Debnath et al., 2005). Furthermore, autophagic programmed cell death has now been demonstrated during development of Drosophila and Dictyostelium discoideum (Berry and Baehrecke, 2007, Lam et al., 2008).
Autophagy is a highly conserved survival response to growth limiting conditions, in which cellular components are sequestered, degraded and released for re-cycling by autophagosomes (Yorimitsu and Klionsky, 2005). It is genetically regulated by a family of Atg genes (Mizushima, 2007) which have homologues in humans (e.g. human ortholog of Atg6-Beclin1). The role of autophagy in cancer remains controversial. Constitutive autophagy may be a necessary homeostatic process which removes damaged organelles and re-cycles macromolecules thus protecting against cancer (Mizushima et al., 2008). However, when a cancer is established—autophagy may take on new roles—it may help cancer cells survive in response to growth limiting conditions such as nutrient depletion, hypoxia, absence of growth factor and presence of cytotoxic drug (Jin and White, 2008, Degenhardt et al., 2006, Amaravadi et al., 2007). The induction of excessive autophagy may also be the major cell death mechanism that takes over when apoptosis is unavailable (Scarlatti et al., 2009). Autophagic cell death has been reported to be induced in malignant gliomas, ovarian and breast carcinoma by the chemotherapeutic agents temozolomide and Tamoxifen (Kanzawa et al., 2003, Kanzawa et al., 2004, Takeuchi et al., 2005, Opipari et al., 2004).
It is an object of the invention to overcome at least one of the above-referenced problems.